3 4-Dihydro-1h-isoquinoloin-2-yl-derivatives

ABSTRACT

The present invention relates to novel compounds of formula I wherein the variable groups are as defined in the claims or a pharmaceutically acceptable acid addition salt thereof. The compounds of the invention are NK2 antagonists.

FIELD OF THE INVENTION

The compounds of the present invention belong to a novel class of 3,4-dihydro-1H-isoquinolin-2-yl-derivatives having affinity for the neurokinin 2 (NK2) receptor. The compounds are NK2-antagonists and are useful in the treatment of those diseases where an NK2-receptor is implicated like asthma and a CNS-disease. These novel 3,4-dihydro-1H-isoquinolin-2-yl-derivatives are capable of penetrating the blood brain barrier and therefore useful in treating a variety of CNS diseases.

BACKGROUND OF THE INVENTION

Three tachykinins, Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) are widely distributed throughout the peripheral and central nervous systems. The biological effects of these neuropeptides are carried out via binding to their preferred receptors, NK1, NK2 and NK3 (Guard, S. and Watson, S. P. Neurochem. Int. 1991, 18, 149). Substance P displays highest affinity for the NK1 receptors, whereas NKA and NKB bind preferentially to NK2 and NK3 receptors, respectively. The selectivities of the endogenous ligands for their respective receptors are not absolute (reviewed in Regoli, D. et al. Pharmacol. Rev. 1994, 46, No. 4, 551 plus Bremer, A. A. et al. Eur J Pharmacol 2001, 423, 143). The three receptor subtypes belong to the G-protein-coupled receptor super family and have been cloned in various species including mice, rats and humans (Giardina, G. A. M. et al. Drugs of the Future 1997, 22, 1235 and references herein).

Activation of the tachykinin receptors influences a broad array of biological actions, including pain transmission, vasodilation, smooth muscle contraction, secretion of saliva, bronchoconstriction, activation of the immune system (inflammatory pain), neurogenic inflammation and neurotransmission (Patacchini, R. et Maggi, C. A. Eur J Pharmacol. 2001, 429, 13; Longmore, J. et al. Can J Physiol Pharmacol 1997, 75, 612; Giardina, G. A. M. et al. Drugs of the Future 1997, 22, 1235 and references herein). Expression of NK2 receptors in human is somewhat controversial. The receptor is generally expressed in low amounts in CNS, and autoradiographic studies have failed to show NK2 receptors in the human brain. A recent reverse transcription-polymerase chain reaction (RT-PCR) study, however, has revealed a detectable expression of NK2 receptor mRNA in various human brain regions including caudate nucleus, putamen, hippocampus, substantia nigra and cerebral cortex (Bensaid, M et al. Neurosci Lett 2001, 303, 25).

Up-regulation of the preprotachykinin (PPT) genes and mRNAs for the neurokinin receptors occurs both in animal models of disease (Fischer, A. et al. J Clin Invest 1996, 98, 2284) and in human diseases, such as asthma (Adcock, I. M. et al. J Mol Endocrino 1993, 11, 1).

NK antagonists have been and are under investigations for the treatment of a vast amount of both CNS related and peripheral diseases. A number of pre-clinical studies have been performed to assess the involvement of NK1 and NK2 receptors mediation and modulation of diseases related to anxiety and/or depression (Griebel, G. Et al. Psychopharmacology, 2001, 158, 241; Walsh, D. M. et al. Psychopharmacology 1995, 121, 186; Rupniak, N. M. et al. Neuropharmacology 2000, 39, 1413; Rupniak, N. M. et Kramer, M. S. TiPS 1999, 20, 485;; Giardina, G. A. M. et al. Drugs of the Future 1997, 22, 1235, and references in these).

These studies indicate that NK2 antagonists will be useful in treating or preventing a variety of brain disorders including depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalised anxiety disorder, social anxiety disorder, panic anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder, psychosis, and Huntington's disease as well as Parkinson's disease, adjustment disorders, pain, emesis, migraine, epilepsia, obesity, asthma and cerebrovascular disease. However, peripheral diseases such as inflammation, inflammatory bowel disease, hypertension, arthritis, cardiovascular diseases, neuritis, neuralgia, urticaria, incontinence, gastrointestinal diseases, influenza, allergy, pulmonary allergy and carcinoma/tumoral growth may also be addressed by NK2 antagonists.

U.S. Pat. No. 3,994,891 discloses tetrahydroisoquinolines of the general formula

wherein R is hydrogen or methyl, and G is NH or CH₂. The dihydroxy compounds are described as effective vasodilators, whereas the dimethoxy compounds are intermediates in the manufacture of the dihydroxy compounds.

Hence, there is a desire for novel compounds that are antagonists at the NK2 receptor.

SUMMARY OF THE INVENTION

The objective of the present invention is to provide compounds that are antagonists at the NK2 receptor.

A further objective of the present invention is to provide compounds with such activities which have improved solubility, metabolic stability and/or bioavailability compared to prior art compounds.

Accordingly, the present invention relates to novel compounds of formula I

wherein

-   R¹ is a group R¹¹CO—, R¹¹CS—, R¹¹SO₂—, R¹¹OCO—, R¹¹SCO— or     R¹¹CO—CR¹²R¹³— wherein R¹¹ is C₁₋₁₂-alkyl, C₂₋₆-alkenyl,     C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl,     aryl-C₁₋₆-alkyl, heteroaryl, heteroaryl-C₁₋₆-alkyl,     tetrahydropyranyl, 1,2,3,4-tetrahydronaphtalenyl, or     4H-benzo[1,3]dioxinyl optionally substituted with halogen wherein     each of said C₁₋₆-alkyl, aryl, heteroaryl and C₃₋₈-cycloalkyl groups     independently are unsubstituted or substituted with one or more     substituents selected from the group comprising halogen, C₁₋₆-alkyl,     C₁₋₆-alkoxy, aryl-C₁₋₆-alkoxy, C₁₋₆-alkylsulfanyl, aryl and aryloxy     wherein said aryl and aryloxy independently are unsubstituted or     substituted with one or more halogen, and R¹² and R¹³ independently     are hydrogen or C₁₋₆-alkyl; or R¹ is a group R¹⁴R¹⁵NCO—, R¹⁴R¹⁵NCS—,     wherein R¹⁴ and R¹⁵ are independently hydrogen, C₁₋₆-alkyl,     C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,     C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl or aryl-C₁₋₆-alkyl, wherein each of     said C₁₋₆-alkyl, aryl and C₃₋₈-cycloalkyl groups independently are     unsubstituted or substituted with one or more substituents selected     from the group comprising halogen, C₁₋₆-alkyl and C₁₋₆-alkoxy, or     R¹⁴ and R¹⁵ together with the N-atom to which they are linked, form     a pyrrolidinyl, piperidinyl or perhydroazepinyl group; -   R² is selected from hydrogen, trifluoromethyl and C₁₋₆-alkyl; -   R³-R⁶, R^(7a), R^(7b), R^(8a) and R^(8b) are independently selected     from hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl,     C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino,     C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl,     aminocarbonyl, C₁₋₆-alkylaminocarbonyl,     di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₄-alkoxy, C₁₋₆-alkylthio, hydroxy,     trifluoromethyl, trifluoromethylsulfonyl and C₁₋₆-alkylsulfonyl; -   m is 2-6; -   R⁹ is benzyl, benzoyl, 2,3-dihydrobenzofuranyl or mono- or bicyclic     aryl or heteroaryl wherein each benzyl, benzoyl, aryl or heteroaryl     optionally is substituted with one or more substituents selected     from halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,     C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,     di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,     C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,     C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl,     fluoromethyl and trifluoromethylsulfonyl; -   Q is C, N or CR¹⁰; -   wherein R¹⁰ is selected from hydrogen, halogen, cyano, nitro,     C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,     C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,     di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,     C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,     C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl,     fluoromethyl, trifluoromethylsulfonyl, a group —NR³⁰COR³¹ wherein     R³⁰ is hydrogen or C₁₋₆-alkyl and R³¹ is C₁₋₆-alkyl, a group —COOR¹⁶     wherein R¹⁶ is hydrogen or C₁₋₆-alkyl, or a group —CONR¹⁷R¹⁵ wherein     R¹⁷ and R¹⁸ independently are selected from hydrogen and C₁₋₆-alkyl     or R¹⁷ and R¹⁸ together with the nitrogen to which they are attached     form a piperidinyl, piperazinyl or morpholinyl, wherein said     piperidinyl, piperazinyl and morpholinyl is unsubstituted or     substituted with a C₁₋₆-alkyl; -   or R⁹ and R¹⁰ together with the carbon to which they are attached     form a cyclic structure selected from the group comprising:     wherein Q′ is the carbon shared with the piperidine ring, so that     said cyclic structure together with said piperidine ring form a     spiro structure; and -   X, Y, and Z are independently chosen from O; NR¹⁹; CR²³R²⁴; S(O)_(n)     and a bond; wherein R¹⁹ is selected from hydrogen, C₁₋₆-alkyl,     C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,     C₃₋₈-cycloalkyl-C₁₋₆-alkyl, trifluoromethyl, acyl, thioacyl and     trifluoromethylsulfonyl, or R¹⁹ is a group R²⁰SO₂—, R²⁰OCO— or     R²⁰SCO— wherein R²⁰ is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,     C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl or aryl, or R¹⁹ is a     group R²¹R²²NCO— or R²¹R²²NCS—, wherein R²¹ and R²² are     independently hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,     C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, or aryl, wherein said     aryl is unsubstituted or substituted with one or more substituents     selected from C₁₋₆-alkyl or halogen; or R²¹ and R²² together with     the N-atom to which they are linked, form a pyrrolidinyl,     piperidinyl or perhydroazepinyl group; R²³ and R²⁴ are independently     selected from hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl,     C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,     C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, heteroaryl, wherein said aryl is     unsubstituted or substituted with one or more substituents selected     from C₁₋₆-alkyl or halogen, amino, C₁₋₆-alkylamino, a group NR²⁵R²⁶     wherein R²⁵ and R²⁶ are independently selected from C₁₋₆-alkyl     C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl,     di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,     trifluoromethyl, trifluoromethylsulfonyl and C₁₋₆-alkylsulfonyl or     R²⁵ and R²⁶ together with the N-atom to which they are linked, form     a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group,     or R²³ and R²⁴ together is oxo; and n is 0, 1 or 2; provided that no     more than one of X, Y and Z may be a bond, and provided that two     adjacent groups X, Y or Z may not at the same time be selected from     O and S; and -   A¹, A², A³ and A⁴ are independently selected from N and CR²⁷ wherein     R²⁷ is hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl,     C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,     C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl,     di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,     trifluoromethyl, difluoromethyl, fluoromethyl,     trifluoromethylsulfonyl C₁₋₆-alkylsulfonyl amino or a group NR²⁸R²⁹     wherein R²⁸ and R²⁹ are independently selected from hydrogen and     C₁₋₆-alkyl or R²⁸ and R²⁹ together with the N-atom to which they are     linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or     morpholinyl group; provided that only one of A¹, A², A³ and A⁴ may     be N; and -   the dotted line emanating from Q is a bond when Q is C, and no bond     when Q is CR¹⁰ or N;     or a pharmaceutically acceptable acid addition salt thereof

DETAILED DESCRIPTION OF THE INVENTION

The C₁₋₁₂-alkyl groups defined for R¹¹ are preferably selected from C₁₋₁₀-alkyl, more preferred C₁₋₈-alkyl, and most preferred C₃₋₈-alkyl.

In one embodiment, the present invention relates to such compounds wherein Q is CR¹⁰, and R⁹ and R¹⁰ together with the carbon to which they are attached form a bicyclic structure:

wherein Q′ is the carbon shared with the piperidine ring, so that said bicyclic structure together with said piperidine ring form a spiro structure; and

-   X, Y and Z are independently chosen from O; NR¹⁹; CR²³R²⁴ and S(O)n     wherein R¹⁹ is selected from hydrogen, C1₋₆-alkyl, C₂₋₆-alkenyl,     C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,     trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or R¹⁹     is a group R²⁰SO₂—, R²⁰OCO— or R²⁰SCO— wherein R²⁰ is C₁₋₆-alkyl,     C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,     C₃₋₈-cycloalkyl-C₁₋₆-alkyl or aryl, or R¹⁹ is a group R²¹R²²NCO—,     R²¹R²²NCS—, wherein R²¹ and R²² are independently hydrogen,     C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,     C₃₋₈-cycloalkyl-C₁₋₆-alkyl or aryl, wherein said aryl is     unsubstituted or substituted with one or more substituents selected     from C₁₋₆-alkyl or halogen; or R²¹ and R²² together with the N-atom     to which they are linked, form a pyrrolidinyl, piperidinyl or     perhydroazepinyl group; R²³ and R²⁴ are independently selected from     hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl,     C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl,     heteroaryl, wherein said aryl is unsubstituted or substituted with     one or more substituents selected from C₁₋₆-alkyl or halogen, amino,     C₁₋₆-alkylamino, a group NR²⁵R²⁶ wherein R²⁵ and R²⁶ are     independently selected from C₁₋₆-alkyl or R²⁵ and R²⁶ together with     the N-atom to which they are linked, form a pyrrolidinyl,     piperidinyl, perhydroazepinyl or morpholinyl group,     C¹⁻⁶-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl,     di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,     trifluoromethyl, trifluoromethylsulfonyl, and C₁₋₆-alkylsulfonyl or     R²³ and R²⁴ together is oxo; and n is 0, 1 or 2; and a bond;     provided that no more than one of X, Y and Z may be a bond, and     provided that two adjacent groups X, Y or Z may not at the same time     be selected from O and S; and     -   A¹, A², A³ and A⁴ are independently selected from N and CR²⁷         wherein R²⁷ is hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl,         C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,         C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, a group NR²⁸R²⁹ wherein R²⁸         and R²⁹ are independently selected from hydrogen and C₁₋₆-alkyl         or R²⁸ and R²⁹ together with the N-atom to which they are         linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or         morpholinyl group, C₁₋₆-alkylcarbonyl, aminocarbonyl,         C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆alkyl)aminocarbonyl,         C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl,         difluoromethyl, fluoromethyl, trifluoromethylsulfonyl or         C₁₋₆-alkylsulfonyl; provided that only one of A¹, A², A³ and A⁴         may be N.

In a preferred embodiment, the present invention relates to such compounds wherein X, Y and Z are selected from one of the combinations: X is oxygen, Y is a bond and Z is CR²³R²⁴; X is CR²³R²⁴, Y is a bond and Z is oxygen; X is NR¹⁹, Y is a bond and Z is CR²³R²⁴; X is CR²³R²⁴, Y is a bond and Z is NR¹⁹; X is CO, Y is a bond and Z is NR¹⁹; X is SO₂, Y is a bond and Z is NR¹⁹; X is SO, Y is a bond and Z is NR¹⁹; X is CR²³R²⁴, Y is a bond and Z is S; X is CR²³R²⁴, Y is a bond and Z is SO; X is CR²³R²⁴, Y is a bond and Z is SO₂; wherein R¹⁹ is hydrogen, acetyl or methylsulfonyl and R²³ and R²⁴ are independently selected from hydrogen, methyl, isobutyl, cyclohexyl and 4-fluorophenyl.

In another preferred embodiment, the present invention relates to such compounds wherein —X—Y-Z- together form a group selected from: —O—CR²³R²⁴—, —CR²³R²⁴—O—, —NR¹⁹—CR²³R²⁴—, —CR²³R²⁴—NR¹⁹—, —CO—NR¹⁹—, —SO₂—NR¹⁹—, —SO—NR¹⁹—, —CR²³R²⁴—S—, —CR²³R²⁴—SO—, —CR²³R²⁴—SO₂—; wherein R¹⁹ is hydrogen, acetyl or methylsulfonyl tyl and R²³ and R²⁴ are independently selected from hydrogen, methyl, isobutyl, cyclohexyl and 4-fluorophenyl.

In another preferred embodiment, the present invention relates to such compounds wherein A³ is N or CR²⁷ wherein R²⁷ is halogen, cyano, nitro, a group NR²⁸R²⁹ wherein R²⁸ and R²⁹ are independently selected from hydrogen and C₁₋₆-alkyl or R²⁸ and R²⁹ together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl or C₁₋₆-alkylsulfonyl.

In another preferred embodiment, the present invention relates to such compounds wherein A¹, A², A³ and A⁴ are independently selected from CR²⁷ wherein R²⁷ is as defined above.

In a more preferred embodiment, the present invention relates to such compounds wherein bicyclic structure described above is selected from the group comprising:

wherein R^(19′) is acetyl or methylsulfonyl, R^(23′) is hydrogen or methyl, R^(27′) is hydrogen or fluoro, R^(27″) is hydrogen, fluoro, methyl or isopropyl, R^(27′″) is hydrogen, fluoro or trifluoromethyl.

In another embodiment, the present invention relates to such compounds wherein R⁹ and R¹⁰ together with the carbon to which they are attached form a cyclic structure selected from the group comprising:

wherein Q′ is the carbon shared with the piperidine ring, so that said cyclic structure together with said piperidine ring form a spiro structure

In yet another embodiment, the present invention relates to such compounds wherein R⁹ is benzyl, benzoyl, 2,3-dihydrobenzofuran-7-yl or mono- or bicyclic aryl or heteroaryl wherein each benzyl, benzoyl, aryl or heteroaryl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.

In yet another embodiment, the present invention relates to such compounds wherein R⁹ is 2,3-dihydrobenzofuran-7-yl, benzyl or benzoyl wherein said benzyl or benzoyl is unsubstituted or substituted with one or more halogens in the phenyl groups, or R⁹ is mono- or bicyclic aryl or heteroaryl selected from the group comprising phenyl, indolyl, pyridyl, thiophenyl and benzisoxazolyl, wherein each aryl or heteroaryl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino, di-(C₁₋₆alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.

In a preferred embodiment, the present invention relates to such compounds wherein said mono- or bicyclic aryl or heteroaryl is selected from the group comprising phenyl, indol-3-yl and benzisoxazol-3-yl wherein said phenyl, indol-3-yl or benzisoxazol-3-yl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C1₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.

In an even more preferred embodiment, the present invention relates to such compounds wherein said optional substituents are selected from the group comprising halogen, phenyl and methyl.

In yet another embodiment, the present invention relates to such compounds wherein Q is CR¹⁰ wherein R¹⁰ is selected from hydrogen, C₁₋₆-alkylcarbonyl, hydroxy, a group —NR³⁰COR³¹ wherein R³⁰ is hydrogen or C₁₋₆-alkyl and R³¹ is C₁₋₆-alkyl, a group —COOR¹⁶ wherein R¹⁶ is C₁₋₆-alkyl, or a group —CONR¹⁷R¹⁸ wherein R¹⁷ and R¹⁸ together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl are unsubstituted or substituted with a C₁₋₆-alkyl.

In a preferred embodiment, the present invention relates to such compounds wherein R¹⁰ is selected from hydrogen, acetyl, hydroxy, a group —NR³⁰COR³¹ wherein R³⁰ is hydrogen and R³¹ is methyl, a group —COOR¹⁶ wherein R¹⁶ is ethyl, or a group —CONR¹⁷R¹⁸ wherein R¹⁷ and R¹⁸ together with the nitrogen to which they are attached form a piperidinyl or a 4-methylpiperazinyl.

In another preferred embodiment, the present invention relates to such compounds wherein m is 2, 3 or 4, more preferred m is 2.

In yet another embodiment, the present invention relates to such compounds wherein R¹ is a group R¹¹CO—, R¹¹OCO— wherein R¹¹ is C₃₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, phenyl, phenyl-C₁₋₆-alkyl, pyridyl, furanyl, benzo[1,2,5]oxadiazolyl, quinoxalinyl, benzo[b]thiophenyl or naphthalenyl wherein each of said C₃₋₆-alkyl, phenyl, pyridyl and furanyl groups independently are unsubstituted or substituted with one or more substituents selected from the group comprising halogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, phenyl and phenoxy wherein said phenyl and phenoxy independently are unsubstituted or substituted with one halogen; or R¹ is a group R¹⁴R¹⁵NCO—, wherein R¹⁴ and R¹⁵ are independently hydrogen, C₁₋₆-alkyl, aryl, or aryl-C₁₋₆-alkyl, wherein each of said C₁₋₆-alkyl and aryl groups independently are unsubstituted or substituted with one substituent selected from the group comprising halogen and C₁₋₆-alkoxy.

In yet another embodiment, the present invention relates to such compounds wherein R² is hydrogen.

In yet another embodiment, the present invention relates to such compounds wherein R³ is hydrogen.

In yet another embodiment, the present invention relates to such compounds wherein R⁴ is hydrogen or methoxy.

In yet another embodiment, the present invention relates to such compounds wherein R⁵ is hydrogen or methoxy.

In yet another embodiment, the present invention relates to such compounds wherein R⁶ is hydrogen.

In yet another embodiment, the present invention relates to such compounds wherein R^(7a) and R^(7b) is hydrogen.

In yet another embodiment, the present invention relates to such compounds wherein R^(8a) and R^(8b) is hydrogen.

Preferred compounds of the invention are compounds number 1-209 as disclosed in the experimental section as well as the compounds in the following list:

-   1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone, -   1-cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, -   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, -   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, -   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, -   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, -   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, -   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, -   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, -   1-cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone, -   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone, -   1-(4-fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone, -   1-cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone, -   1-cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, -   1-cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, -   1-cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, -   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, -   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, -   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, -   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, -   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone, -   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone, -   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone, -   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone, -   1-cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl)-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, -   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone, -   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-methanone, -   1-(4-fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, -   1-cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-methanone, -   1-cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, -   1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone, -   1-cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]ethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, -   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl)-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, -   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, -   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, -   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, -   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, -   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, -   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, -   1-cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone, -   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-cyclopentyl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone, -   1-(4-fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone, -   1-cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone, -   1-cyclopentyl-1-(1-(2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, -   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, -   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, -   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, -   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, -   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, -   1-cyclopentyl-1-(1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, -   1-(4-fluorophenyl)-1-(1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, -   1-cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone, -   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl)-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone, -   1-(4-fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone, -   1-(4-fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, -   1-cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,     and -   1-cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone.

The compounds of the invention are NK₂ receptors antagonists having a human NK₂ binding affinity (IC50) of 5 μM or less, typically of 1 μM or less, preferably of 200 nM or less, more preferred of 50 nM or less and most preferred of 10 μM or less.

Accordingly, the compounds of the invention are considered useful in treating a variety of CNS diseases such as depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalised anxiety disorder, social anxiety disorder, panic anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder, psychosis and Huntington's disease as well as Parkinson's dementia, adjustment disorders, pain, emesis, migraine, epilepsia, obesity and cerebrovascular disease.

In particular, the compounds of the invention are considered useful in the treatment of depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalised anxiety disorder, social anxiety disorder, panic anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder and psychosis.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.

In a further aspect, the present invention provides the use of a compound of formula I as defined above or an acid addition salt thereof for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders.

The compounds of the general formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention. Throughout the specification and claims, reference to specific compounds refers to the racemates unless otherwise indicated.

The term C₁₋₆-alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, and 2-methyl-1-propyl. The terms C₁₋₈-alkyl, C₁₋₁₀-alkyl and C₁₋₁₂-alkyl, respectively, refer similarly to branched or unbranched alkyl group having from one to eight, ten or twelve carbon atoms inclusive, respectively.

Similarly, C₂₋₆-alkenyl and C₂₋₆-alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond, respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

The term C₃₋₈-cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.

Halogen means fluoro, chloro, bromo or iodo.

As used herein, the term acyl refers to a formyl, C₁₋₆-alkylcarbonyl, arylcarbonyl, aryl-C₁₋₆-alkylcarbonyl, C₃₋₈-cycloalkylcarbonyl or a C₃₋₈-cycloalkyl-C₁₋₆-alkyl-carbonyl group, and the term thioacyl is the corresponding acyl group, in which the carbonyl group is replaced with a thiocarbonyl group.

The terms C₁₋₆-alkoxy, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkylsulfonyl, C₁₋₆-alkylamino, C₁₋₆-alkylcarbonyl, and the like, designate such groups in which the C₁₋₆-alkyl and the C₃₋₈-cycloalkyl group are as defined above.

The term aryl refers to a carbocyclic aromatic group, such as phenyl or naphthyl, in particular phenyl.

The term heteroaryl refers to 5-membered monocyclic rings such as 1H-tetrazolyl, 3H-1,2,3-oxathiazolyl, 3H-1,2,4-oxathiazolyl, 3H-1,2,5-oxathiazolyl, 1,3,2-oxathiazolyl, 1,3,4-oxathiazolyl, 1,4,2-oxathiazolyl, 3H-1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,4,2-dioxazolyl, 3H-1,2,3-dithiazolyl, 3H-1,2,4-dithiazolyl, 1,3,2-dithiazolyl, 1,4,2-dithiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1H -1,2,3-triazolyl, 1H -1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1H-imidazolyl, 1H-pyrazolyl, 1H-pyrrolyl, furanyl, thienyl, 1H-pentazole; 6-membered monocyclic rings such as 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, 4H-1,3,5-oxathiazinyl, 1,4,2-oxathiazinyl, 1,4,3-oxathiazinyl, 1,2,3-dioxazinyl, 1,2,4-dioxazinyl, 4H-1,3,2-dioxazinyl, 4H-1,3,5-dioxazinyl, 1,4,2-dioxazinyl, 2H-1,5,2-dioxazinyl, 1,2,3-dithiazinyl, 1,2,4-dithiazinyl, 4H-1,3,2-dithiazinyl, 4H-1,3,5-dithiazinyl, 1,4,2-dithiazinyl, 2H-1,5,2-dithiazinyl, 2H-1,2,3-oxadiazinyl, 2H-1,2,4-oxadiazinyl, 2H-1,2,5-oxadiazinyl, 2H-1,2,6-oxadiazinyl, 2H-1,3,4-oxadiazinyl, 2H-1,3,5-oxadiazinyl, 2H-1,2,3-thiadiazinyl, 2H-1,2,4-thiadiazinyl, 2H-1,2,5-thiadiazinyl, 2H-1,2,6-thiadiazinyl, 2H-1,3,4-thiadiazinyl, 2H-1,3,5-thiadiazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 2H-1,2-oxazinyl, 2H-1,3-oxazinyl, 2H-1,4-oxazinyl, 2H-1,2-thiazinyl, 2H-1,3-thiazinyl, 2H-1,4-thiazinyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridyl, 2H-pyranyl, 2H-thiinyl; and to bicyclic rings such as 3H-1,2,3-benzoxathiazolyl, 1,3,2-benzodioxazolyl, 3H-1,2,3-benzodithiazolyl, 1,3,2-benzodithiazolyl, benzfurazanyl, 1,2,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, 1H-benzotriazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzothiazolyl, 1H-benzimidazolyl, 1H-indazolyl, 3H-1,2-benzoxathiolyl, 1,3-benzoxathiolyl, 3H-2,1-benzoxathiolyl, 3H-1,2-benzodioxolyl, 1,3-benzodioxolyl 3H-1,2-benzodithiolyl, 1,3-benzodithiolyl, 1H-indolyl, 2H-isoindolyl, benzofuranyl, isobenzofuranyl, 1-benzothienyl, 2-benzothienyl, 1H-2,1-benzoxazinyl, 1H-2,3-benzoxazinyl, 2H-1,2-benzoxazinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 2H-3,1-benzoxazinyl, 1H-2,1-benzothiazinyl, 1H-2,3-benzothiazinyl, 2H-1,2-benzothiazinyl, 2H-1,3-benzothiazinyl, 2H-1,4-benzothiazinyl, 2H-3,1-benzothiazinyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, isoquinolyl, quinolyl, 1H-2-benzopyranyl, 2H-1-benzopyranyl, 1H-2-benzothiopyranyl or 2H-1-benzothiopyranyl.

The acid addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The pharmaceutical compositions of this invention, or those which are manufactured in accordance with this invention, may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.

Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg.

The total daily dose is usually in the range of about 0.05-500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.

The compounds of the invention may be prepared as follows:

-   -   1) Alkylating a piperazine, piperidine or tetrahydropyridine of         formula III with an alkylating derivative of formula II:         wherein R¹-R⁹ and Q are as previously defined and L is a leaving         group such as e.g. halogen, mesylate or tosylate;     -   2) Reductive alkylation of an amine of formula III with a         reagent of formula IV:         wherein R¹-R⁹ and Q are as previously defined and E is an         aldehyde or an activated carboxylic acid;     -   3) Acylating an amine of formula V by the use of a carboxylic         acid and a coupling reagent, an activated ester, an acid         chloride, an isocyanate, carbamoyl chloride or by a two-step         procedure by treatment with phosgene followed by addition of an         amine:         wherein R¹-R⁹ and Q are as previously defined, whereupon the         compound of formula I is isolated as the free base or a         pharmaceutically acceptable acid addition salt thereof.

The alkylation according to method 1) is conveniently performed in an organic solvent such as a suitably boiling alcohol or ketone, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine) at reflux temperature. Alternatively, the alkylation can be performed at a fixed temperature, which is different from the boiling point, in one of the above-mentioned solvents or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO), or N-methylpyrrolidin-2-one (NMP), preferably in the presence of a base. The alkylating agents of formula II can be prepared by methods analogues to those described in the examples or can be synthesised by applying methods described in standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. New York, namely under reaction conditions such as those which are known and suitable for such reactions. The amines of formula III are either commercially available or have been described in the literature or can be prepared by methods analogues to those described in the literature e.g. Marxer et al. J. Org. Chem. 1975, 40, 1427, by Parham et al. J. Org. Chem. 1976, 41, 2628 and by Bauer et al. J. Med. Chem. 1976, 19, 1315, Maligres et al. Tetrahedron 1997, 53, 10983, and by Cheng et al. Tet. Lett. 1997, 38, 1497, Chen, Meng-Hsin; Abraham, John A. Tetrahedron Lett. 1996, 37, 5233-5234 and Slade, P. D. et al. J. Med. Chem. 1998, 41, 1218-1235, or can be synthesised by methods described in standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. New York, namely under reaction conditions such as those which are known and suitable for such reactions.

The reductive alkylation according to method 2) is performed by standard literature methods or as described in standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. New York, namely under reaction conditions such as those which are known and suitable for such reactions. The reaction can be performed in two steps, e.g. coupling of amines of formula III with a reagent of formula IV by standard methods via the carboxylic acid chloride, activated esters or by the use of carboxylic acids in combination with a coupling reagents such as e.g. dicyclohexyl carbodiimide, followed by reduction of the resulting amide with lithium aluminium hydride or alane. The carboxylic acids of formula IV are either commercially available or can be prepared by methods analogues to those described in the literature (e.g. Tet. Lett. 37, 1996, pp. 5453-5456; Tet. Lett. 35, 1994, pp. 6567-6570; J. Med. Chem. 25, 1982, pp. 1235-1240; Synthesis 1987, pp. 474-477).

The acylation according to method 3) is conveniently performed by standard methods via the carboxylic acid chloride, activated esters or by the use of carboxylic acids in combination with coupling reagents such as e.g. dicyclohexyl carbodiimide. When the acylating reagent is carbamoyl chlorides or isocyanates, the acylation produces urea derivatives. The urea derivatives can also be prepared by a two-step procedure consisting of treatment with phosgene followed by addition of an amine.

The intermediate compounds of formula V are prepared as described in methods 1) and 2), wherein R²-R⁹, Q, L and E are as previously defined, and R¹ is a protection group. This protection group may be chosen from those protection group generally used for protection of amino groups. Those skilled in the art will know to select appropriate protection groups and how to protect and deprotect the amines with these protection groups.

Experimental Section

Melting points were determined on a Büchi SMP-20 apparatus and are uncorrected. Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with IonSpray source and Shimadzu LC-8A/SLC-10A LC system. The LC conditions (C18 column 4.6×30 mm with a particle size of 3.5 μm) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (90:10:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 4 min at 2 mL/min. Purity was determined by integration of the UV trace (254 nm). The retention times, R_(t), are expressed in minutes.

Mass spectra were obtained by an alternating scan method to give molecular weight information. The molecular ion, MH+, was obtained at low orifice voltage (5-20V) and fragmentation at high orifice voltage (100-200V).

Preparative LC-MS-separation was performed on the same instrument. The LC conditions (C18 column 20×50 mm with a particle size of 5 μm) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) to water/acetonitrile/trifluoroacetic acid (5:95:0.03) in 7 min at 22.7 mL/min. Fraction collection was performed by split-flow MS detection.

¹H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250 instrument. Deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9% D) were used as solvents. TMS was used as internal reference standard. Chemical shift values are expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: s=singlet, d=doublet, tt=triplet, q=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet, dq=double quartet, tt=triplet of triplets, m=multiplet. NMR signals corresponding to acidic protons are generally omitted. For column chromatography silica gel of type Kieselgel 60, 230-400 mesh ASTM was used. For ion-exchange chromatography (SCX, 1 g, Varian Mega Bond Elut®, Chrompack cat. No. 220776) was used. Prior use of the SCX-columns was pre-conditioned with 10% solution of acetic acid in methanol (3 mL).

Preparation of Intermediates

Alkylating Reagents of the Formula II

1. (RS)-1-(2-Bromo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid-tert-butyl ester Tetrahydrosioquinolinic acid (10 g) was suspended in tetrahydrofuran THF (100 mL). Triethyl amine (9.1 mL) and di-tert-butyl dicarbonate (14.3 g) was added and the mixture stirred at room temperature for 16 h. The mixture was concentrated in vacuo, redissolved in ethyl acetate (250 mL) and washed twice with and aqueous 0.5 M KHSO₄-solution (200 mL), dried over magnesium sulphate and evaporated in vacuo to give 1-carboxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester in quantitative yield as a clear oil which crystallised upon standing. The protected amino acid was dissolved in dry tetrahydrofuran under nitrogen, cooled to 0° C. and 1M borane in tetrahydrofuran (41.5 mL) was added slowly under nitrogen during 15 min. The mixture was warmed to room temperature and stirred for 1 h. Excess borane was carefully destroyed by slow addition of 50 mL of a 1:1 mixture of water/tetrahydrofuran. The mixture was made alkaline to pH=12 by addition of saturated potassium carbonate and extracted with diethylether (2×50 mL). The combined organic phase were dried (magnesium sulphate) and evaporated in vacuo to give 1-(2-Hydroxy-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as a clear oil (8.4 g). The protected aminoalcohol was dissolved in dry tetrahydrofuran (150 mL) together with triethylamine (5.6 mL) and cooled to 0° C. under nitrogen. Methanosulfonyl chloride (2.64 mL) in dry THF (30 mL) was added dropwise during 15 min and the mixture was warmed to room temperature and stirred for 30 min. After filtration and concentration in vacuo the clear oily residue was dissolved in acetone (300 mL), lithium bromide (14.6 g) was added and the mixture was heated to reflux for 1 h. The mixture was filtered, evaporated in vacuo and the product purified by column chromatography on silicagel using as eluent ethyl acetate/heptane (1:1) and fractions containing the product was pooled and evaporated in vacuo to give (RS)-1-(2-Bromo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid-tert-butyl ester as a clear oil (8 g) which crystallised upon standing.

The following compound was prepared in a similar way:

-   (RS)-1-(2-Bromo-ethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid-tert-butyl ester     Piperidines of the Formula III

The piperidine-derivatives of formula III, wherein X is oxygen, Z is CR⁹R¹⁰, Y is a bond, A¹, A² and A⁴ are CH, A³ is CR¹¹, i.e. spiro[isobenzofuran-1(3H),4′-piperidines] are prepared according to the methods described by Marxer et al. J. Org. Chem. 1975, 40, 1427, by Parham et al. J. Org. Chem. 1976, 41, 2628 and by Bauer et al. J. Med. Chem. 1976, 19, 1315.

The following compounds were prepared in a similar way:

-   6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine], -   6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine], -   6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine], -   6-trifluoromethyl-3-methylspiro[isobenzofuran-1(3H),4′-piperidine], -   5-methylspiro[isobenzofuran-1(3H),4′-piperidine], -   6-fluoro-3-isobutylspiro[isobenzofuran-1(3H),4′-piperidine], -   6-fluoro-3-cyclohexylspiro[isobenzofuran-1(3H),4′-piperidine] and -   6-fluoro-3-(4-fluorophenyl)spiro[isobenzofuran-1(3H),4′-piperidine]

The piperidine-derivatives of formula III, wherein X is CR⁹R¹⁰, Z is NR⁸, Y is a bond, A¹, A² and A⁴ are CH, A³ is CR¹¹ and R¹¹ is fluoro or trifluoromethyl, are prepared according to the methods described by Maligres et al. Tetrahedron 1997, 53, 10983, and by Cheng et al. Tet. Lett. 1997, 38, 1497.

The following compound was prepared in a similar way:

-   1-Acetyl-5-fluoro-spiro[2,3-dihydro-1H-indol-3,4′-piperidine].

The piperidine-derivatives of formula III, wherein the X is CR⁹R¹⁰, Z is oxygen, Y is a bond, A¹, A² and A⁴ are CH, A³ is CR¹¹, i.e. 2,3-dihydro-spiro(benzofuran-3,4′-piperidines), are prepared according to the methods described by Chen, Meng-Hsin; Abraham, John A. Tetrahedron Lett. 1996, 37, 5233-5234 and Slade, P. D. et al. J. Med. Chem. 1998, 41, 1218-1235.

The following compounds were prepared in a similar way:

-   2,3-Dihydro-5-fluorospiro[benzofiuran-3,4′-piperidine] and -   2,3-dihydro-5,6-difluorospiro[benzofuran-3,4′-piperidine]

The substituents R⁸-R¹¹ are introduced by applying suitably substituted starting compounds to methods analogous to the above mentioned.

Amines of the Formula V

An amine of formula V was prepared by the following procedure:

A mixture of an amine of formula III (1 mmol), (RS)-1-(2-Bromo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid-tert-butyl ester (1.3 mmol) and potassium carbonate (1.3 mmol) in acetonitrile (20 mL) were heated to 85° C. for 6 h. The mixture was cooled to room temperature and evaporated in vacuo to give an yellow oily residue. The product was redissolved in dichloromethane (10 mL) and anisole (0.26 mL) and trifluoroacetic acid (10 mL) were added and the mixture stirred at room temperature for 90 min. The mixture was evaporated in vacuo. The product was either purified by chromatography or used directly in the next step without purification.

The following compounds were purified by chromatography before further use:

-   (RS)-1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-1,2,3,4-tetrahydro-isoquinoline -   (RS)-1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-1,2,3,4-tetrahydroisoquinoline     Enantiomeric Forms of Amines of the Formula V -   Enantiomer 1 and enantiomer 2 of     N-(4-(3-Fluoro-phenyl)-1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-piperidin-4-yl}acetamide

Racemic N-{4-(3-fluoro-phenyl)-1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-piperidin-4-yl}acetamide was subjected to resolution by chiral HPLC using a Gilson SF3 supercritical fluid chromatography system equipped with chiralcelOD columns (4.6 mm×25 cm for analytical and 10 mm×25 cm for preparative runs). The particle size in the columns was 10 μm. A solution of the racemic compound N-{4-(3-fluoro-phenyl)-1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-piperidin-4-yl)acetamide (1 g) in methanol (1 mL) was injected in 40 μL portions on a preparative column. The column was eluted with carbondioxide-modifier (75:25). The modifier was 2-propanol with diethylamine (0.5%) and trifluoracetic acid (0.5%). The flow was 18.9 mL/min at 20 Mpa. Fraction collection was triggered by UV-detection (210 nM). The fractions containing the separate products were pooled and evaporated in vacuo which gave the enantiomers. The first eluted enantiomer is called Enantiomer 1 and the second eluted is called Enantiomer 2 of N-{4-(3-fluoro-phenyl)-1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-piperidin-4-yl}acetamide. The enantiomers were measured by HPLC to have an enantiomeric excess higher than 95%.

The following enantiomers were prepared in a similar way:

-   Enantiomer 1 and enantiomer 2 of     N-(4-(phenyl)-1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-piperidin-4-yl}acetamide

EXAMPLES Preparation of the Compounds of the Invention

The compounds of the present invention were prepared by one of two general methods:

Method A: Alkylating a Piperidine of Formula III with an Alkylating Derivative of Formula II:

A mixture of a piperidine of formula III (1 mmol), (RS)-1-(2-Bromo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid-tert-butyl ester (1.3 mmol) and potassium carbonate (1.3 mmol) in acetonitrile (20 mL) were heated to 85° C. for 6 h. The mixture was cooled to room temperature and evaporated in vacuo. The product was purified by chromatography either on silicagel using as eluent ethylacetate/triethylamine (99:1) or by purified by HPLC. Fractions containing the product were pooled and evaporated in vacuo.

Method B: Acylating an Amine of Formula V by the Use of a Carboxylic Acid and a Coupling Reagent, an Activated Ester, an Acid Chloride or an Isocyanate:

An amine of formula V (prepared as described above; 1 mmol) and triethylamine (5 mmol) were dissolved in anhydrous acetonitrile (10 mL). An appropriately substituted acid chloride (5 mmol) was added and the reaction mixture stirred at room temperature for 30 min. Methanol (0.5 mL) was added to the reaction mixture followed by evaporation in vacuo. The product was purified by chromatography either on silicagel using ethylacetate/triethylamine (99:1) as eluent or by HPLC. Fractions containing the product were pooled and evaporated in vacuo and characterised by HPLC-UV-ELSD-MS. The measured HPLC-retention time, the measured molecular mass and UV- and ELSD-purities are shown in table 1.

The following compounds were made by the methods indicated in table 1. analytical data are shown in table 1.

Compound

-   1.     1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone -   2.     1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   3.     1-(2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid phenethyl-amide -   4.     1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenylmethanone -   5.     1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-fluoro-phenyl)methanone -   6.     1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3-phenyl-propan-1-one -   7.     1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid (3-chloro-propyl)amide -   8.     1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid (2-methoxy-phenyl)amide -   9.     1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid tert-butyl ester -   10.     3-Chloro-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2,2-dimethyl-propan-1-one -   12.     1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   13.     1-[2-(4-Chloro-phenoxy)-pyridin-3-yl]-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   14.     1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid tert-butyl ester -   15.     1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenylmethanone -   16.     1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-p-tolylmethanone -   17.     1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-methoxy-phenyl)methanone -   18.     1-Cycloheptyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   19.     1-(2-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   20.     1-(2-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   21.     1-(4-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   22.     1-(4-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   23.     1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid phenethyl amide -   24.     1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-methoxy-phenyl)methanone -   25.     1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3-phenyl-propan-1-one -   26.     2-Ethyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one -   27.     1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-methoxy-phenyl)methanone -   28.     1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2-phenylethanone -   29.     3-Cyclohexyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one -   30.     2-(4-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)ethanone -   31.     1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid (3,4-dichloro-phenyl)amide -   32.     1-Cyclopropyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   33. 1-(1-{2-[6-Fluorospiro[isobenzofuran-1     (3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-pyridin-3-yl-methanone -   34.     1-[5-(4-Chloro-phenyl)-2-methyl-furan-3-yl]-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   35.     2-(4-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)ethanone -   36.     1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-propan-1-one -   37.     1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid (2-ethyl-phenyl)amide -   38.     N-[1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide -   39.     1-Cyclopentyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidin-1′-yl]]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   40.     1-Cycloheptyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone -   41.     N-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl)acetamide -   42.     1-Cycloheptyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   43.     1-(4-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   44.     1-Cycloheptyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   45.     1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-piperidin-1-ylmethanone -   46.     1-(4-Fluorophenyl)-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   47.     1-Cycloheptyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   48.     1-Cycloheptyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   49.     1-Cyclopentyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   50.     1-Cyclopentyl-1-{1-[spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone -   51.     1-Cyclopentyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   52.     1-(4-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   53.     1-(2-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   54.     1-Cycloheptyl-1-(1-{2-[spiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   55.     1-Cycloheptyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   56.     1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone -   57.     1-Cyclopentyl-1-(1-{2-[5-isopropylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   58.     N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide -   59.     1-Cycloheptyl-1-{1-[2-(4-phenylpiperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone -   60.     1-Cycloheptyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   61.     1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   62.     1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   63.     1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   64.     1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone -   65.     1-[1-(2-{2-[1-(4-Fluorophenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenylpiperidin-4-yl]-1-piperidin-1-yl-methanone -   66.     1-Cyclopentyl-1-(1-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   67.     8-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one -   68.     1-Cycloheptyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   69.     1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]-1-(4-methyl-piperazin-1-yl)methanone -   70.     1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidine-4-carboxylic     acid ethyl ester -   71.     1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-ethanone -   72.     1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   73.     1-Cyclopentyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   74.     1-(1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)ethanone -   75.     1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   76.     1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone -   77.     1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-1-(4-fluoro-phenyl)methanone -   78.     1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-(4-methyl-piperazin-1-yl)methanone -   79.     1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-cyclopentylmethanone -   80.     1-(4-Fluoro-phenyl)-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   81.     1-(4-Fluorophenyl)-1-(1-{2-[piro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   82.     1-Cyclopentyl-1-(1-{2-[4-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   83.     1-(2-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   84.     N-[4-(3-Fluoro-phenyl)-1-(2-{2-[1-(4-fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-piperidin-4-yl]-acetamide -   85.     1-(2-Fluorophenyl)-1-{1-[spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone -   86.     1-Cycloheptyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   87.     1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-piperidin-1-ylmethanone -   88.     1-{1-[2-(4-Benzyl-piperidin-1-yl)-ethyl-3,4-dihydro-H-isoquinolin-2-yl}-1-cycloheptylmethanone -   89.     1-(2-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   90.     1-(1-{2-[(Chloro-trifluoromethyl-phenyl)-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone -   91.     1-(1-{2-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone -   92.     1-Cycloheptyl-1-(1-{2-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   93.     1-(1-{2-[4-(7-Chloro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-cyclopentylmethanone -   94.     1-Cyclopentyl-1-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   95.     1-(1-{2-[4-(2,3-Dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone -   96.     N-[1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide -   97.     1-(4-Fluoro-phenyl)-1-{1-[2-(4-phenyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone -   98.     1-(1-{2-[4-(6-Chloro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone -   99.     1-(4-Fluoro-phenyl)-1-(1-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   100.     1-Cycloheptyl-1-{1-[spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl}methanone -   101.     N-(1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide -   102.     1-(1-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-fluoro-phenyl)methanone -   103.     1-cycloheptyl-1-(1-{2-[spiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   104.     1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidine-4-carboxylic     acid ethyl ester -   105.     1-(1-{2-[4-(4-Dimethylamino-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone -   106.     1-Cyclopentyl-1-(1-{2-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   107.     1-[1-(2-{2-[1-(4-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquiinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]ethanone -   108.     1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]ethanone -   109.     1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]-1-piperidin-1-yl-methanone -   110.     1-Cyclopentyl-1-{1-[2-(4-phenyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone -   111.     1-(2-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone -   112.     1-(4-Fluoro-phenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   113.     1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone -   114.     3,3-Dimethyl-[1-{2-[spiro(5-fluoro-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one -   115.     Cyclohexyl-[1-{2-[spiro(5-fluoro-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone -   116.     Cyclohexyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   117.     Cyclohexyl-[1-{2-[spiro(benzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone -   118.     Cyclohexyl-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   119.     N-{1-[2-(2-Cyclohexanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-phenyl-piperidin-4-yl}-acetamide -   120.     3,3-Dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one -   121.     Cyclohexyl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   122.     Cyclohexyl-(1-{2-[4-(4-dimethylamino-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   123.     3-Phenyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propanone -   124.     (1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl-methanone -   125.     2-Phenoxy-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-ethan-1-one -   126.     Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   127.     Cyclohexyl-(1-{2-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   128.     2-Propyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-pentan-1-one -   129.     2,2-Dimethyl-3-chlor-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one -   130.     Cyclohexyl-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   131.     3,3-Dimethyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one -   132.     Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   133.     2-Ethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one -   134.     2-Benzyloxy-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-ethan-1-one -   135.     Benzo[1,2,5]oxadiazol-5-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone -   136.     (1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl-methanone -   137.     1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one -   138.     3,5,5-Trimethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-hexan-1-one -   139.     3,5,5-Trimethyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one -   140.     2-Phenoxy-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-ethan-1-one -   141.     (1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-(2,2-dichloro-cyclopropyl)-methanone -   142.     2-Benzyloxy-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-ethan-1-one -   143.     1-(1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one -   144.     1-(1-{2-[4-(2,3-Dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one -   145.     3,5,5-Trimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one -   146.     2,2-Dimethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one -   147.     3-Cyclohexyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one -   148.     Furan-2-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone -   149.     N-(4-Phenyl-1-{2-[2-(3,5,5-trimethyl-hexanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-acetamide -   150.     Quinoxalin-2-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone -   151.     3-Cyclohexyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one -   152.     Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   153.     Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   154.     (Tetrahydro-pyran-4-yl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   155.     2-Propyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-pentan-1-one -   156.     2-Ethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one -   157.     3-Phenyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one -   158.     3,3-Dimethyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one -   159.     (1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(2,2-dichloro-cyclopropyl)-methanone -   160.     1,2,3,4-tetrahydro-naphthalene-2-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   161.     (4-Methylsulfanyl-phenyl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   162.     3,5,5-Trimethyl-1(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one -   163.     3-Phenyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one -   164.     Furan-2-yl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   165.     2-Benzyloxy-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone -   166.     1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2-phenoxy-ethanone -   167.     Quinoxalin-2-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   168.     2,2-Dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one -   169.     (2,2-Dichloro-cyclopropyl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   170.     4-Methylsulfanyl-phenyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   171.     (2,2-Dichloro-cyclopropyl)-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   172.     1-(1-{2-[4-(4-Isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3,5,5-trimethyl-hexan-1-one -   173.     2,2-Dichloro-cyclopropyl-(1-{2-[spiro(isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   174.     N-(4-Phenyl-1-{2-[2-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-acetamide -   175.     Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(4-chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone -   176.     N-(1-{2-[2-(3,3-Dimethyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-acetamide -   177.     3-Chloro-2,2-dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one -   178.     Tetrahydro-pyran-4-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one

The following compounds were made as enantiomers by method B starting from Enantiomer 2 of the corresponding amines of formula V. Analytical data are shown in table 1.

Compound

-   179.     N-(4-(3-Fluoro-phenyl)-1-{2-[2-(2-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide     (Enantiomer) -   180.     N-(4-(3-Fluoro-phenyl)-1-{2-[2-(2-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide     (Enantiomer) -   181.     N-[1-{2-[2-(4-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide     (Enantiomer) -   182.     N-[1-{2-[2-(4-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide     (Enantiomer) -   183.     N-[1-{2-[2-(4-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide     (Enantiomer) -   184.     N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-isopropyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide     (Enantiomer) -   185.     N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-methyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide     (Enantiomer) -   186.     N-[1-{2-[2-(3-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide     (Enantiomer) -   187.     N-[1-{2-[2-(2-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide     (Enantiomer) -   188.     N-(1-{2-[2-(4-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide     (Enantiomer) -   189.     N-(1-{2-[2-(2,4-Dichloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide     (Enantiomer) -   190.     N-[1-{2-[2-(2,4-Dichloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide     (Enantiomer) -   191.     N-[1-{2-[2-(Benzo[1,2,5]oxadiazole-5-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide     (Enantiomer) -   192.     N-(4-(3-Fluoro-phenyl)-1-{2-[2-(naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide     (Enantiomer) -   193.     N-[1-[2-(2-Cyclopentanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide     (Enantiomer) -   194.     N-(1-{2-[2-(4-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide     (Enantiomer) -   195.     N-[1-{2-[2-(Benzo[b]thiophene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide     (Enantiomer) -   196.     N-[1-{2-[2-(6-Fluoro-4H-benzo[1,3]dioxine-8-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]acetamide     (Enantiomer) -   197.     N-[1-{2-[2-(3-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]acetamide     (Enantiomer) -   198.     N-[1-{2-[2-(2-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]acetamide     (Enantiomer) -   199.     N-(1-{2-[2-(4-Methyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide     (Enantiomer) -   200.     N-[1-{2-[2-(2-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide     (Enantiomer) -   201.     N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide     (Enantiomer) -   202.     N-(1-{2-[2-(3-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl}-4-phenyl-piperidin-4-yl)acetamide     (Enantiomer) -   203.     N-(1-{2-[2-(4-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide     (Enantiomer) -   204.     N-{1-[2-(2-Cycloheptanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-phenyl-piperidin-4-yl}-acetamide     (Enantiomer) -   205.     N-(1-{2-[2-(3-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide     (Enantiomer) -   206.     2-N-(4-(3-Fluoro-phenyl)-1-{2-[2-(3-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide     (Enantiomer) -   207.     N-(4-(3-Fluoro-phenyl)-1-{2-[2-(thiophene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide     (Enantiomer) -   208.     N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-pyrazol-1-yl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide     (Enantiomer)

209. N-(1-{2-[2-(Naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide (Enantiomer) TABLE 1 Measured molecular mass (M + H⁺), measured HPLC-retention time (RT, min) and UV- and ELSD-purities (%) and synthesis method. RT UV-purity ELSD-purity Synthesis compound M + H⁺ min. (%) (%) method 1 500.3 2.34 84.41 100 B 2 474.4 2.38 83.5 100 B 3 496.3 2.45 75.89 100 B 4 481.9 2.29 83.81 100 B 5 500.2 2.29 83.54 100 B 6 510 2.46 84.14 100 B 7 497.4 2.29 100 100 B 8 525.4 2.40 89.67 100 B 9 478.2 2.20 75.37 99.26 A 10 497.1 2.36 75.37 99.26 B 12 463 2.31 100 100 B 13 598.1 2.45 93.85 100 B 14 467 2.43 73.81 96.61 B 15 471.2 2.21 93.09 100 B 16 485 2.34 86.3 100 B 17 501.2 2.27 94.08 100 B 18 491.1 2.54 100 100 B 19 488.9 2.22 84.77 100 B 20 504.9 2.27 77.86 100 B 21 489.2 2.25 80.99 100 B 22 505.1 2.39 85.64 100 B 23 514.2 2.42 79.04 100 B 24 501.3 2.25 83.93 99.53 B 25 499.1 2.42 91.88 100 B 26 465.1 2.34 97.12 100 B 27 501.1 2.25 82.81 100 B 28 485.2 2.27 72.97 100 B 29 505.2 2.73 71.89 100 B 30 502.8 2.31 74.17 100 B 31 554.2 2.60 95.47 100 B 32 435.2 2.06 86.69 100 B 33 472 1.80 95.32 100 B 34 585 2.81 96.53 100 B 35 519 2.44 89.59 100 B 36 437.3 2.13 91.14 100 B 37 514.2 2.40 85.04 100 B 38 520.3 2.29 71.77 76.11 B 39 477.4 2.43 91.78 100 B 40 514.3 2.33 91.25 99.32 B 41 502.3 2.35 70.93 83.59 B 42 551.3 2.44 90.64 100 B 43 503.1 2.37 74.38 100 B 44 550.1 2.50 73.67 95.11 B 45 528.3 2.44 93.37 79.93 B 46 548.2 2.22 94.88 100 B 47 498.3 2.66 74.25 96.35 B 48 513.3 2.77 100 97.34 B 49 537.1 2.33 89.23 100 B 50 486.4 2.12 99.47 100 B 51 522.3 2.29 100 100 B 52 563.1 2.27 72.61 100 B 53 489.2 2.23 76.61 100 B 54 473.6 2.51 70.49 82.63 B 55 565.3 2.55 72.19 100 B 56 479.2 2.74 74.67 83.39 B 57 487.3 2.66 82.69 99.27 B 58 492.2 2.08 85.05 100 B 59 445.5 2.58 70.23 73.14 B 60 505.2 2.65 71.04 76.63 B 61 485.1 2.57 88.72 100 B 62 523.4 2.23 100 100 B 63 549.3 2.19 93.44 100 B 64 502.4 2.29 91.44 100 B 65 554.3 2.38 93.61 100 B 66 435.3 2.38 72.75 93.86 B 67 515.3 2.51 77.67 78.14 B 68 601.3 2.63 81.38 97.64 B 69 569.3 1.65 76.77 88.30 B 70 517.3 2.67 79.03 86.76 B 71 487.4 2.50 72.35 95.17 B 72 573.5 2.42 90.45 100 B 73 470.4 2.45 83.20 100 B 74 459.4 2.27 92.31 100 B 75 599.3 2.36 96.26 98.55 B 76 477.2 2.40 100 93.03 B 77 491.3 2.51 86.66 73.72 B 78 631.5 1.84 75.78 100 B 79 451.1 2.50 86.14 100 B 80 511.1 2.48 100 100 B 81 471.3 2.23 92.66 100 B 82 463.3 2.36 100 100 B 83 563.1 2.24 90.29 100 B 84 518.2 2.03 95.48 100 B 85 512.2 2.02 94.94 88.11 B 86 610.5 2.41 94.60 98.31 B 87 616.2 2.56 89.81 100 B 88 459.3 2.69 71.44 73.94 B 89 599.2 2.33 91.53 100 B 90 623.4 2.65 87.37 98.35 B 91 555.3 2.44 89.31 100 B 92 503.2 2.90 71.70 70.84 B 93 490.2 2.48 100 100 B 94 459.2 2.42 83.29 100 B 95 485.3 2.33 94.29 100 B 96 580.5 2.22 96.44 100 B 97 443.2 2.25 98.80 100 B 98 516 2.42 90.05 100 B 99 461.2 2.29 100 100 B 100 574.4 2.26 99.42 100 B 101 474.4 2.02 100 100 B 102 502.3 2.23 94.60 100 B 103 533.1 2.41 87.36 97.35 B 104 489.4 2.46 79.39 100 B 105 486.4 1.65 88.94 100 B 106 459.5 2.74 81.14 100 B 107 485.4 2.21 94.86 100 B 108 485 2.16 70.08 70.13 B 109 554.4 2.34 70.00 74.91 B 110 417.2 2.35 92.41 100 B 111 549.4 2.14 95.35 100 B 112 507.5 2.45 88.27 98.43 B 113 489.6 2.33 89.20 97.90 B 114 464.6 2.39 97.56 100 B 115 476.6 2.44 97.18 100 B 116 472.7 2.53 98.22 100 B 117 458.6 2.40 86.63 100 B 118 483.7 2.53 99.38 100 B 119 487.7 2.13 95.52 100 B 120 486.6 2.62 94.23 100 B 121 498.6 2.66 98.51 100 B 122 473.7 1.75 94.26 100 B 123 498.6 2.44 97.66 100 A 124 609.1 2.54 97.77 100 B 125 500.6 2.32 93.9 98.82 B 126 508.6 2.37 98.82 100 B 127 472.7 2.83 95.08 100 B 128 492.7 2.63 97.33 100 B 129 485 2.29 94.23 99.4 B 130 472.7 2.52 95.96 100 B 131 460.7 2.49 96.36 100 B 132 534.6 2.48 94.21 99.15 B 133 486.6 2.58 86.65 100 B 134 510.7 2.41 75.55 96.08 B 135 512.6 2.29 98.04 100 B 136 465.1 2.58 96.36 100 B 137 453.1 2.54 97.52 100 B 138 506.7 2.78 98.11 100 B 139 502.7 2.88 77.28 94.4 B 140 496.6 2.39 97.44 100 B 141 491.9 2.44 99.44 99.2 B 142 514.6 2.34 91.48 98.85 B 143 597.1 2.49 97.94 100 B 144 460.7 2.49 95.22 100 B 145 528.7 2.98 98.91 100 B 146 450.6 2.28 100 100 B 147 526.7 2.92 96.57 99.25 B 148 460.5 2.10 96.13 99.34 B 149 517.8 2.50 99.13 100 B 150 522.6 2.26 92.92 99.26 B 151 504.7 2.73 97.79 100 B 152 508.6 2.33 99.37 100 B 153 519.6 2.33 99.06 100 B 154 500.6 2.19 96 99.4 B 155 514.7 2.85 93.87 100 B 156 464.6 2.36 91.14 100 B 157 520.6 2.64 94.34 99.05 B 158 471.7 2.51 97.9 100 B 159 635.9 2.39 96.68 98.58 B 160 520.7 2.69 92.98 99.42 B 161 538.7 2.62 97.24 98.81 B 162 513.8 2.88 95.64 100 B 163 494.7 2.52 98.25 100 B 164 482.5 2.32 91.14 100 B 165 521.7 2.41 93.78 100 B 166 489.1 2.45 97.97 100 B 167 518.7 2.34 87.58 97.31 B 168 472.6 2.50 94.41 99.01 B 169 525.4 2.52 98.4 98.78 B 170 512.7 2.50 98.1 99.2 B 171 499.5 2.37 98.66 99.01 B 172 502.8 3.15 96.92 100 B 173 485.5 2.28 86.08 99.43 B 174 535.7 2.32 89.96 99.01 B 175 501 2.42 98.67 100 B 176 475.7 2.09 97.47 100 B 177 507 2.52 90.73 100 B 178 478.6 1.94 91.92 100 B 179 530.3 2.01 89.59 99.31 B 180 550.2 2.32 96.42 98.14 B 181 534.2 2.15 99.1 100 B 182 578.2 2.18 99.05 100 B 183 518.2 2.00 98.42 99.38 B 184 542.4 2.34 93.23 99.9 B 185 514.4 2.09 99.41 100 B 186 534.2 2.11 98.69 100 B 187 578.3 2.04 71.31 100 B 188 562.2 2.13 95.59 100 A 189 550.2 2.22 88.21 95.21 B 190 568.4 2.22 86.21 98.71 B 191 542.4 2.03 99.09 100 B 192 550.2 2.17 97.37 100 B 193 492.3 2.07 81.75 100 B 194 516.3 2.09 96.4 100 B 195 556.3 2.15 99.36 99.89 B 196 576.3 2.03 96.774 100 B 197 580.4 2.14 98.59 100 B 198 518.2 1.95 82.81 99.74 B 199 496.2 2.15 91.36 99.03 B 200 534.2 2.01 79.14 99.08 B 201 530.3 2.01 99.08 100 B 202 516.3 2.16 94.57 98.33 B 203 500.5 1.97 96.4 100 B 204 502.4 2.25 88.94 100 B 205 562.1 2.20 93.75 96.46 B 206 530.3 2.00 98.7 100 B 207 506.2 1.92 98.2 100 B 208 566.4 1.99 98.45 100 B 209 532.2 2.21 93.74 98.44 B Pharmacological Testing

The compounds of the invention were tested in a well-recognised and reliable test. The test was as follows:

Inhibition of Binding of ¹²⁵I-NKA to Human NK2 Receptors

The compounds of the invention have been found to potently inhibit the binding of ¹²⁵I-NKA to the human NK2 receptor.

By this method, the inhibition by drugs of the binding of ¹²⁵I-NKA to membranes of human cloned NK2 receptors expressed in CHO-cells is determined in vitro.

Briefly, the affinity of the compounds was measured by their ability to displace ¹²⁵I-NKA, by incubating hNK2 expressing CHO membranes with compound and radioligand at room temperature for 60 minutes. Incubation was terminated by rapid filtration through GF/C filters, and filters were counted in a Wallac Trilux Scintillation Counter. The IC50 values for the compounds No. 1-209, exemplified above, was determined to be 200 nM or less. For the majority of the compounds the IC50 values were 50 nM or less, and for a large group of the compounds the IC50 values were 10 nM or less.

FORMULATION EXAMPLES

The pharmaceutical formulations of the invention may be prepared by conventional methods in the art.

For example: Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.

Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilising the solution and filling it in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.

Typical examples of recipes for the formulation of the invention are as follows:

1) Tablets containing 5.0 mg of a compound of the invention calculated as the free base: Compound 1a or 1b 5.0 mg Lactose 60 mg Maize starch 30 mg Hydroxypropylcellulose 2.4 mg Microcrystalline cellulose 19.2 mg Croscarmellose Sodium Type A 2.4 mg Magnesium stearate 0.84 mg

2) Tablets containing 0.5 mg of a compound of the invention calculated as the free base: Compound 1a or 1b 0.5 mg Lactose 46.9 mg Maize starch 23.5 mg Povidone 1.8 mg Microcrystalline cellulose 14.4 mg Croscarmellose Sodium Type A 1.8 mg Magnesium stearate 0.63 mg

3) Syrup containing per millilitre: Compound 1a or 1b 25 mg Sorbitol 500 mg Hydroxypropylcellulose 15 mg Glycerol 50 mg Methyl-paraben 1 mg Propyl-paraben 0.1 mg Ethanol 0.005 mL Flavour 0.05 mg Saccharin sodium 0.5 mg Water ad 1 mL

4) Solution for injection containing per millilitre: Compound 1a or 1b 0.5 mg Sorbitol 5.1 mg Acetic Acid 0.05 mg Saccharin sodium 0.5 mg Water ad 1 mL 

1. A 3,4-dihydro-1H-isoquinolin-2-yl-derivative of formula I

wherein R¹ is a group R¹¹CO—, R¹¹CS—, R¹¹SO₂—, R¹¹OCO—, R¹¹SCO— or R¹¹CO—CR¹²R¹³— wherein R¹¹ is C₁₋₁₂-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆alkyl, aryl, aryl-C₁₋₆-alkyl, heteroaryl, heteroaryl-C₁₋₆-alkyl, tetrahydropyranyl, 1,2,3,4-tetrahydronaphtalenyl, or 4H-benzo[1,3]dioxinyl optionally substituted with halogen wherein each of said C₁₋₆-alkyl, aryl, heteroaryl and C₃₋₈-cycloalkyl groups independently are unsubstituted or substituted with one or more substituents selected from the group comprising halogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, aryl-C₁₋₆-alkoxy, C₁₋₆-alkylsulfanyl, aryl and aryloxy wherein said aryl and aryloxy independently are unsubstituted or substituted with one or more halogen, and R¹² and R¹³ independently are hydrogen or C₁₋₆-alkyl; or R¹ is a group R¹⁴R¹⁵NCO—, R¹⁴R¹⁵NCS—, wherein R¹⁴ and R¹⁵ are independently hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl or aryl-C₁₋₆-alkyl, wherein each of said C₁₋₆-alkyl, aryl and C₃₋₈-cycloalkyl groups independently are unsubstituted or substituted with one or more substituents selected from the group comprising halogen, C₁₋₆-alkyl and C₁₋₆-alkoxy, or R¹⁴ and R¹⁵ together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepinyl group; R² is selected from hydrogen, trifluoromethyl and C₁₋₆-alkyl; R³-R⁶, R^(7a), R^(7b), R^(8a) and R^(8b) are independently selected from hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C₁₋₆-alkylsulfonyl; m is 2-6; R⁹ is benzyl, benzoyl, 2,3-dihydrobenzofuranyl or mono- or bicyclic aryl or heteroaryl wherein each benzyl, benzoyl, aryl or heteroaryl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl; Q is C, N or CR¹⁰; wherein R¹⁰ is selected from hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl, a group —NR³⁰COR³¹ wherein R³⁰ is hydrogen or C₁₋₆-alkyl and R³¹ is C₁₋₆-alkyl, a group —COOR¹⁶ wherein R¹⁶ is hydrogen or C₁₋₆-alkyl, or a group —CONR¹⁷R¹⁸ wherein R¹⁷ and R¹⁸ independently are selected from hydrogen and C₁₋₆-alkyl or R¹⁷ and R¹⁸ together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl is unsubstituted or substituted with a C₁₋₆-alkyl; or R⁹ and R¹⁰ together with the carbon to which they are attached form a cyclic structure selected from the group comprising:

wherein Q′ is the carbon shared with the piperidine ring, so that said cyclic structure together with said piperidine ring form a spiro structure; and X, Y, and Z are independently chosen from O; NR¹⁹; CR²³R²⁴; S(O)_(n) and a bond; wherein R¹⁹ is selected from hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆-alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or R¹⁹ is a group R²⁰SO₂—, R²⁰OCO— or R²⁰SCO— wherein R²⁰ is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl or aryl, or R¹⁹ is a group R²¹R²²NCO— or R²¹R²²NCS—, wherein R²¹ and R²² are independently hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, or aryl, wherein said aryl is unsubstituted or substituted with one or more substituents selected from C₁₋₆-alkyl or halogen; or R²¹ and R²² together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepinyl group; R²³ and R²⁴ are independently selected from hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, heteroaryl, wherein said aryl is unsubstituted or substituted with one or more substituents selected from C₁₋₆-alkyl or halogen, amino, C₁₋₆-alkylamino, a group NR²⁵R²⁶ wherein R²⁵ and R²⁶ are independently selected from C₁₋₆-alkyl C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C₁₋₆-alkylsulfonyl or R²⁵ and R²⁶ together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, or R²³ and R²⁴ together is oxo; and n is 0, 1 or 2; provided that no more than one of X, Y and Z may be a bond, and provided that two adjacent groups X, Y or Z may not at the same time be selected from O and S; and A¹, A², A³ and A⁴ are independently selected from N and CR²⁷ wherein R²⁷ is hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl C₁₋₆-alkylsulfonyl amino or a group NR²⁸R²⁹ wherein R²⁸ and R²⁹ are independently selected from hydrogen and C₁₋₆-alkyl or R²⁸ and R²⁹ together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group; provided that only one of A¹, A², A³ and A⁴ may be N; and the dotted line emanating from Q is a bond when Q is C, and no bond when Q is CR¹⁰ or N; or a pharmaceutically acceptable acid addition salt thereof
 2. A compound according to claim 1 characterised in that Q is CR¹⁰, and R⁹ and R¹⁰ together with the carbon to which they are attached form a bicyclic structure:

wherein Q′ is the carbon shared with the piperidine ring, so that said bicyclic structure together with said piperidine ring form a spiro structure; and X, Y and Z are independently chosen from O; NR¹⁹; CR²³R²⁴ and S(O)_(n), wherein R¹⁹ is selected from hydrogen, C1₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or R¹⁹ is a group R²⁰SO₂—, R²⁰OCO— or R²⁰SCO— wherein R²⁰ is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, or aryl, or R¹⁹ is a group R²¹R²²NCO—, R²¹R²²NCS—, wherein R²¹ and R²² are independently hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, or aryl, wherein said aryl is unsubstituted or substituted with one or more substituents selected from C₁₋₆-alkyl or halogen; or R²¹ and R²² together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, or perhydroazepinyl group; R²³ and R²⁴ are independently selected from hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, heteroaryl, wherein said aryl is unsubstituted or substituted with one or more substituents selected from C₁₋₆-alkyl or halogen, amino, C₁₋₆-alkylamino, a group NR²⁵R²⁶ wherein R²⁵ and R²⁶ are independently selected from C₁₋₆-alkyl or R²⁵ and R²⁶ together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl, or morpholinyl group, C₁₋₄-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C₁₋₆-alkylsulfonyl or R²³ and R²⁴ together is oxo; and n is 0, 1 or 2; and a bond; provided that no more than one of X, Y and Z may be a bond, and provided that two adjacent groups X, Y or Z may not at the same time be selected from O and S; and A¹, A², A³ and A⁴ are independently selected from N and CR²⁷ wherein R²⁷ is hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, a group NR²⁸R²⁹ wherein R²⁸ and R²⁹ are independently selected from hydrogen and C₁₋₆-alkyl or R²⁸ and R²⁹ together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl or C₁₋₆-alkylsulfonyl; provided that only one of A¹, A², A³ and A⁴ may be N.
 3. A compound according to claim 2 characterised in that X, Y and Z are selected from one of the combinations: X is oxygen, Y is a bond and Z is CR²³R²⁴; X is CR²³R²⁴, Y is a bond and Z is oxygen; X is NR¹⁹, Y is a bond and Z is CR²³R²⁴; X is CR²³R²⁴, Y is a bond and Z is NR¹⁹; X is CO, Y is a bond and Z is NR¹⁹; X is SO₂, Y is a bond and Z is NR¹⁹; X is SO, Y is a bond and Z is NR¹⁹; X is CR²³R²⁴, Y is a bond and Z is S; X is CR²³R²⁴, Y is a bond and Z is SO; X is CR²³R²⁴, Y is a bond and Z is SO₂; wherein R¹⁹ is hydrogen, acetyl or methylsulfonyl and R²³ and R²⁴ are independently selected from hydrogen, methyl, isobutyl, cyclohexyl and 4fluorophenyl.
 4. A compound according to claim 2 characterised in that —X—Y-Z- together form a group selected from: —O—CR²³R²⁴—, —CR²³R²⁴—O—, —NR¹⁹—CR²³R²⁴—, —CR²³R²⁴—NR¹⁹—, —CO—NR¹⁹—, —SO₂—NR¹⁹—, —SO—NR¹⁹—, —CR²³R²⁴—S—, —CR²³R²⁴—SO—, —CR²³R²⁴—SO₂—; wherein R¹⁹ is hydrogen, acetyl or methylsulfonyl and R²³ and R²⁴ are independently selected from hydrogen, methyl, isobutyl, cyclohexyl and 4-fluorophenyl.
 5. A compound according to any of claims 2 to 4 characterised in that A³ is N or CR²⁷ wherein R²⁷ is halogen, cyano, nitro, a group NR²⁸R²⁹ wherein R²⁸ and R²⁹ are independently selected from hydrogen and C₁₋₆alkyl or R²⁸ and R²⁹ together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl, or C₁₋₆-alkylsulfonyl.
 6. A compound according to any of claims 2 to 5 characterised in that A¹, A², A³ and A⁴ are independently selected from CR²⁷ wherein R²⁷ is as defined above.
 7. A compound according to claim 2 characterised in that said bicyclic structure is selected from the group comprising:

wherein R^(19′) is acetyl or methylsulfonyl, R^(23′) is hydrogen or methyl, R^(27′) is hydrogen or fluoro, R^(27″) is hydrogen, fluoro, methyl or isopropyl, R^(27′″) is hydrogen, fluoro or trifluoromethyl.
 8. A compound according to claim 1 characterised in that R⁹ and R¹⁰ together with the carbon to which they are attached form a cyclic structure selected from the group comprising:

wherein Q′ is the carbon shared with the piperidine ring, so that said cyclic structure together with said piperidine ring form a spiro structure.
 9. A compound according to claim 1 characterised in that R⁹ is benzyl, benzoyl, 2,3-dihydrobenzofuran-7-yl or mono- or bicyclic aryl or heteroaryl wherein each benzyl, benzoyl, aryl or heteroaryl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C1₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.
 10. A compound according to claim 9 characterised in that R⁹ is 2,3-dihydrobenzofuran-7-yl, benzyl or benzoyl wherein said benzyl or benzoyl is unsubstituted or substituted with one or more halogens in the phenyl groups, or R⁹ is mono- or bicyclic aryl or heteroaryl selected from the group comprising phenyl, indolyl, pyridyl, thiophenyl and benzisoxazolyl, wherein each aryl or heteroaryl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C1₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.
 11. A compound according to claim 10 characterised in that said mono- or bicyclic aryl or heteroaryl is selected from the group comprising phenyl, indol-3-yl and benzisoxazol-3-yl wherein said phenyl, indol-3-yl or benzisoxazol-3-yl optionally is substituted with one or more substituents selected from halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C1₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.
 12. A compound according to claim 11 characterised in that said optional substituents are selected from the group comprising halogen, phenyl and methyl.
 13. A compound according to any of claims 9 to 12 characterised in that Q is CR¹⁰ wherein R¹⁰ is selected from hydrogen, C₁₋₆-alkylcarbonyl, hydroxy, a group —NR³⁰COR³¹ wherein R³⁰ is hydrogen or C₁₋₆-alkyl and R³¹ is C₁₋₆-alkyl, a group —COOR¹⁶ wherein R¹⁶ is C₁₋₆-alkyl, or a group —CONR¹⁷R¹⁸ wherein R¹⁷ and R¹⁸ together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl is unsubstituted or substituted with a C₁₋₆-alkyl.
 14. A compound according to claim 13 characterised in that R¹⁰ is selected from hydrogen, acetyl, hydroxy, a group —NR³⁰COR³¹ wherein R³⁰ is hydrogen and R³¹ is methyl, a group —COOR¹⁶ wherein R¹⁶ is ethyl, or a group —CONR¹⁷R¹⁸ wherein R¹⁷ and R¹⁸ together with the nitrogen to which they are attached form a piperidinyl or a 4-methylpiperazinyl.
 15. A compound according to any of claims 1 to 14 characterised in that m is 2, 3 or
 4. 16. A compound according to claim 15 characterised in that m is
 2. 17. A compound according to any of claims 1 to 16 characterised in that R¹ is a group R¹¹CO—, R¹¹OCO— wherein R¹¹ is C₃₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, phenyl, phenyl-C₁₋₆-alkyl, pyridyl, furanyl, benzo[1,2,5]oxadiazolyl, quinoxalinyl, benzo[b]thiophenyl or naphthalenyl wherein each of said C₃₋₄-alkyl, phenyl, pyridyl and furanyl groups independently are unsubstituted or substituted with one or more substituents selected from the group comprising halogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, phenyl and phenoxy wherein said phenyl and phenoxy independently are unsubstituted or substituted with one halogen; or R¹ is a group R¹⁴R¹⁵NCO—, wherein R¹⁴ and R¹⁵ are independently hydrogen, C₁₋₆-alkyl, aryl, or aryl-C₁₋₆-alkyl, wherein each of said C₁₋₆-alkyl and aryl groups independently are unsubstituted or substituted with one substituent selected from the group comprising halogen and C₁₋₆-alkoxy.
 18. A compound according to any of claims 1 to 17 characterised in that R² is hydrogen.
 19. A compound according to any of claims 1 to 18 characterised in that R³ is hydrogen.
 20. A compound according to any of claims 1 to 19 characterised in that R⁴ is hydrogen or methoxy.
 21. A compound according to any of claims 1 to 20 characterised in that R⁵ is hydrogen or methoxy.
 22. A compound according to any of claims 1 to 21 characterised in that R⁶ is hydrogen.
 23. A compound according to any of claims 1 to 22 characterised in that R^(7a) and R^(7b) is hydrogen.
 24. A compound according to any of claims 1 to 23 characterised in that R^(8a) and R^(8b) is hydrogen.
 25. A compound according to claim 1 characterised in that it is selected from the group comprising: 1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone 1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid phenethyl-amide 1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenylmethanone 1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-fluoro-phenyl)methanone 1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3-phenyl-propan-1-one 1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (3-chloro-propyl)amide 1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (2-methoxy-phenyl)amide 1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 3-Chloro-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2,2-dimethyl-propan-1-one 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-[2-(4-Chloro-phenoxy)-pyridin-3-yl]-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenylmethanone 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-p-tolylmethanone 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-methoxy-phenyl)methanone 1-Cycloheptyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(2-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(2-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(4-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(4-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid phenethyl amide 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-methoxy-phenyl)methanone 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3-phenyl-propan-1-one 2-Ethyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-methoxy-phenyl)methanone 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2-phenylethanone 3-Cyclohexyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one 2-(4-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)ethanone 1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (3,4-dichloro-phenyl)amide 1-Cyclopropyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-pyridin-3-yl-methanone 1-[5-(4-Chloro-phenyl)-2-methyl-furan-3-yl]-1(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 2-(4-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)ethanone 1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-propan-1-one 1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (2-ethyl-phenyl)amide N-[1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide 1-Cyclopentyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidin-1′-yl]]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-Cycloheptyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone N-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl)acetamide 1-Cycloheptyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-(4-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-Cycloheptyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-piperidin-1-ylmethanone 1-(4-Fluorophenyl)-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-Cycloheptyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-Cycloheptyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-Cyclopentyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-Cyclopentyl-1-{1-[spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone 1-Cyclopentyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(4-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-(2-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-Cycloheptyl-1-(1-{2-[spiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-Cycloheptyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone 1-Cyclopentyl-1-(1-{2-[5-isopropylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide 1-Cycloheptyl-1-{1-[2-(4-phenylpiperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone 1-Cycloheptyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone 1-[1-(2-{2-[1-(4-Fluorophenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenylpiperidin-4-yl]-1-piperidin-1-yl-methanone 1-Cyclopentyl-1-(1-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 8-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 1-Cycloheptyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]-1-(4-methyl-piperazin-1-yl)methanone 1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidine-4-carboxylic acid ethyl ester 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-ethanone 1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-Cyclopentyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)ethanone 1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-1-(4-fluoro-phenyl)methanone 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-(4-methyl-piperazin-1-yl)methanone 1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-cyclopentylmethanone 1-(4-Fluoro-phenyl)-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1-isoquinolin-2-yl)methanone 1-(4-Fluorophenyl)-1-(1-{2-[piro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-Cyclopentyl-1-(1-{2-[4-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(2-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone N-[4-(3-Fluoro-phenyl)-1-(2-{2-[1-(4-fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-piperidin-4-yl]-acetamide 1-(2-Fluorophenyl)-1-{1-[spiro[2,3-dihydro-1H -indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone 1-Cycloheptyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-piperidin-1-ylmethanone 1-{1-[2-(4-Benzyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-1-cycloheptylmethanone 1-(2-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-(1-{2-[(Chloro-trifluoromethyl-phenyl)-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone 1-(1-{2-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone 1-Cycloheptyl-1-(1-{2-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(1-{2-[4-(7-Chloro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-cyclopentylmethanone 1-Cyclopentyl-1-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-(1-{2-[4-(2,3-Dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone N-[1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide 1-(4-Fluoro-phenyl)-1-{1-[2-(4-phenyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone 1-(1-{2-[4-(6-Chloro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone 1-(4-Fluoro-phenyl)-1-(1-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-Cycloheptyl-1-{1-[spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl}methanone N-(1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide 1-(1-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-fluoro-phenyl)methanone 1-cycloheptyl-1-(1-{2-[spiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidine-4-carboxylic acid ethyl ester 1-(1-{2-[4-(4-Dimethylamino-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone 1-Cyclopentyl-1-(1-{2-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-[1-(2-{2-[1-(4-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]ethanone 1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]ethanone 1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]-1-piperidin-1-yl-methanone 1-Cyclopentyl-1-{1-[2-(4-phenyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone 1-(2-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone 1-(4-Fluoro-phenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone 3,3-Dimethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one Cyclohexyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone Cyclohexyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone Cyclohexyl-[1-{2-[spiro(benzofuran-3H-1 ,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone Cyclohexyl-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone N-{1-[2-(2-Cyclohexanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-phenyl-piperidin-4-yl}-acetamide 3,3-Dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one Cyclohexyl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone Cyclohexyl-(1-{2-[4-(4-dimethylamino-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 3-Phenyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propanone (1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H -isoquinolin-2-yl)-cyclohexyl-methanone 2-Phenoxy-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-ethan-1-one Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone Cyclohexyl-(1-{2-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 2-Propyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-pentan-1-one 2,2-Dimethyl-3-chlor-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one Cyclohexyl-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 3,3-Dimethyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 2-Ethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one 2-Benzyloxy-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-ethan-1-one Benzo[1,2,5]oxadiazol-5-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)]-ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone (1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl-methanone 1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one 3,5,5-Trimethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-hexan-1-one 3,5,5-Trimethyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one 2-Phenoxy-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-ethan-1-one (1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-(2,2-dichloro-cyclopropyl)-methanone 2-Benzyloxy-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-ethan-1-one 1-(1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one 1-(1-{2-[4-(2,3-Dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one 3,5,5-Trimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one 2,2-Dimethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one 3-Cyclohexyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one Furan-2-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone N-(4-Phenyl-1-{2-[2-(3,5,5-trimethyl-hexanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-acetamide Quinoxalin-2-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone 3-Cyclohexyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone (Tetrahydro-pyran-4-yl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 2-Propyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-pentan-1-one 2-Ethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one 3-Phenyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one 3,3-Dimethyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one (1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(2,2-dichloro-cyclopropyl)-methanone 1,2,3,4-tetrahydro-naphthalene-2-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone (4-Methylsulfanyl-phenyl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 3,5,5-Trimethyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one 3-Phenyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one Furan-2-yl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 2-Benzyloxy-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone 1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2-phenoxy-ethanone Quinoxalin-2-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 2,2-Dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one (2,2-Dichloro-cyclopropyl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 4-Methylsulfanyl-phenyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone (2,2-Dichloro-cyclopropyl)-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone 1-(1-{2-[4-(4-Isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3,5,5-trimethyl-hexan-1-one 2,2-Dichloro-cyclopropyl-(1-{2-[spiro(isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone N-(4-Phenyl-1-{2-[2-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-acetamide Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(4-chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone N-(1-{2-[2-(3,3-Dimethyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-acetamide 3-Chloro-2,2-dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one Tetrahydro-pyran-4-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one 1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone, 1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl }-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-Chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, 1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro 1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, 1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, 1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone, 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5chloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone, 1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone, 1-Cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone, 1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone, 1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro1H -indol-3,4′-piperidin-1′-yl]-ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone, 1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone, 1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone, 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-methanone, 1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl)-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-methanone, 1-Cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone, 1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, 1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, 1-(4-Fluorophenyl)-1-{1-[-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, 1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone, 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone, 1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone, 1-Cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone, 1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide, N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, 1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, 1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro 1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, 1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone, 1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone, 1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone, 1-(4-Fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1-isoquinolin-2-yl)-methanone, 1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone, 1-Cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone, and 1-Cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone. or from the group comprising the following enantiomers which are prepared by acylation of Enantiomer 2 of the corresponding amines of formula V,

wherein R²-R⁹ and Q are as defined for formula I; and Enantiomer 2 is the slowly eluting of the enantiomer pair by supercritical HPLC at 20 Mpa on a system comprising chiralcelOD columns and an eluent consisting of carbondioxide (75%), 2-propanol (24.75%), diethylamine (0.125%) and trifluoracetic acid (0.125%): N-(4-(3-Fluoro-phenyl)-1-{2-[2-(2-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide (Enantiomer) N-(4-(3-Fluoro-phenyl)-1-{2-[2-(2-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide (Enantiomer) N-[1-{2-[2-(4-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-[1-{2-[2-(4-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-[1-{2-[2-(4-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-isopropyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide (Enantiomer) N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-methyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide (Enantiomer) N-[1-{2-[2-(3-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-[1-{2-[2-(2-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-(1-{2-[2-(4-Bromo-benzoyl)-1,2,3, 4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide (Enantiomer) N-(1-{2-[2-(2,4-Dichloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide (Enantiomer) N-[1-{2-[2-(2,4-Dichloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-[1-{2-[2-(Benzo[1,2,5]oxadiazole-5-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-(4-(3-Fluoro-phenyl)-1-{2-[2-(naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide (Enantiomer) N-[1-[2-(2-Cyclopentanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-(1-{2-[2-(4-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide (Enantiomer) N-[1-{2-[2-(Benzo[b]thiophene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-[1-{2-[2-(6-Fluoro-4H-benzo[1,3]dioxine-8-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]acetamide (Enantiomer) N-[1-{2-[2-(3-Bromo-benzoyl)-1,2, 3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]acetamide (Enantiomer) N-[1-{2-[2-(2-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]acetamide (Enantiomer) N-(1-{2-[2-(4-Methyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide (Enantiomer) N-[1-{2-[2-(2-Chloro-benzoyl)-1, 2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide (Enantiomer) N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide (Enantiomer) N-(1-{2-[2-(3-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide (Enantiomer) N-(1-{2-[2-(4-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide (Enantiomer) N-{1-[2-(2-Cycloheptanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-phenyl-piperidin-4-yl}-acetamide (Enantiomer) N-(1-{2-[2-(3-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide (Enantiomer) 2-N-(4-(3-Fluoro-phenyl)-1-{2-[2-(3-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide (Enantiomer) N-(4-(3-Fluoro-phenyl)-1-{2-[2-(thiophene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide (Enantiomer) N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-pyrazol-1-yl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide (Enantiomer) N-(1-{2-[2-(Naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide (Enantiomer)
 26. A pharmaceutical composition comprising a compound of any of claims 1 to 25 in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or diluents.
 27. Use of a compound of any of claims 1 to 25 for the manufacture of a pharmaceutical preparation for the treatment of a disorder in the central nervous system.
 28. Use according to claim 27 characterised in that the disorder is selected from the group comprising depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalized anxiety disorder, social anxiety disorder, panic anxiety disorder, post-traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder, psychosis and Huntington's disease as well as Parkinson's dementia, adjustment disorders, pain, emesis, migraine, epilepsia, obesity and cerebrovascular disease.
 29. Use according to claim 28 characterised in that the disorder is selected from the group comprising depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalized anxiety disorder, social anxiety disorder, panic anxiety disorder, post-traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder and psychosis.
 30. Use of a compound of any of claims 1 to 25 in treatment of a disorder in the central nervous system.
 31. Use according to claim 30 characterised in that the disorder is selected from the group comprising depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalised anxiety disorder, social anxiety disorder, panic anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder, psychosis and Huntington's disease as well as Parkinson's dementia, adjustment disorders, pain, emesis, migraine, epilepsia, obesity and cerebrovascular disease.
 32. Use according to claim 31 characterised in that the disorder is selected from the group comprising depression, manic depression, bipolar disorder, dysthymia, mixed anxiety depression, generalized anxiety disorder, social anxiety disorder, panic anxiety disorder, post-traumatic stress disorder, obsessive compulsive disorder, acute stress disorder, phobia, pre-menstrual dysphoric disorder and psychosis. 